Is C8A p.Arg552Gly (c.1654A>G) pathogenic?

C8A p.Arg552Gly (c.1654A>G) is classified Likely benign in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-28). AlphaMissense: likely benign (0.0766); Rare (popmax 0.421%, eas).

How common is C8A p.Arg552Gly (c.1654A>G) in the general population?

C8A p.Arg552Gly (c.1654A>G) is rare (popmax 0.421%, eas) (gnomAD).

What do computational predictors say about C8A p.Arg552Gly (c.1654A>G)?

AlphaMissense predicts likely benign (score 0.0766) — an in-silico prediction, not a clinical call.

C8A p.Arg552Gly

c.1654A>G · rs56334452 · VCV717260

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.421%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0766	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -9.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 1.1, phastCons 0.98
Regional constraint	o/e 1.08	unconstrained · MANE · 63 kb · p 0.034 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.421% East Asian · 189/44,870 alleles

Filtering AF 0.372% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.353%

Overall 0.0127% 205/1,614,210 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.421%	237
Remaining individualsnot grpmax-eligible	0.0112%	8,929
South Asian	0.00878%	11,386
European (non-Finnish)	8.47e-05%	1,180,036

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: C8A
Protein: p.Arg552Gly
Coding: c.1654A>G
MANE Select: NM_000562
dbSNP: rs56334452
Type: single nucleotide variant
Location: chr1:56917615 (GRCh38)
Gene constraint: LOEUF 1.168 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.58 · 11 PDB
Residue 552: a β-strand; the tsp type-1 2 domain; a disulfide bond; a UniProt-annotated variant site (in c8d1)

Full C8A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C8A p.Arg424Ter Pathogenic ★★ same type
C8A p.Arg498Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Glu466Ter Pathogenic ★★ same type
C8A p.Tyr210Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Tyr384Ter Pathogenic/Likely pathogenic ★★ same type
C8A p.Arg107Cys Uncertain significance ★★ ⚠ same type
C8A p.Arg196His Uncertain significance ★★ ⚠ same type
C8A p.Arg207Gln Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/c8a-p-arg552gly (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown